NCAPG confers trastuzumab resistance via activating SRC/STAT3 signaling pathway in HER2-positive breast cancer
NCAPG confers trastuzumab resistance via activating SRC/STAT3 signaling pathway in HER2-positive breast cancer
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NCAPG 通过激活 HER2 阳性乳腺癌的 SRC/STAT3 信号通路赋予曲妥珠单抗耐药性
DOI：
10.1038/s41419-020-02753-x
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发表时间：
2020-07-18
影响因子：
9
通讯作者：
Song, Libing
中科院分区：
文献类型：
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作者：
Jiang, Lili;Ren, Liangliang;Song, Libing
HER2+乳腺癌（BC）具有快速生长、早期复发、早期转移和化疗耐药的特点。曲妥珠单抗是治疗HER2+ BC最有效的药物，可有效降低患者复发和死亡的风险。曲妥珠单抗耐药导致肿瘤复发和转移，导致HER2+ BC预后不良。在本研究中，我们发现染色体凝聚蛋白1复合体亚单位G （NCAPG）的非结构维持在曲珠单抗耐药的HER2+ BC中高度上调。在HER2+ BC患者中，异位NCAPG与肿瘤复发和较短的生存期呈正相关。此外，在体外和体内，NCAPG的过表达促进了HER2+ BC细胞的增殖和抗凋亡能力，而NCAPG的沉默降低了HER2+ BC细胞对曲妥珠单抗的敏感性，这表明NCAPG降低了HER2+ BC细胞对曲妥珠单抗的敏感性，并可能赋予了曲妥珠单抗耐药性。此外，我们的研究结果表明，NCAPG通过磷酸化SRC和增强STAT3的核定位和激活来触发一系列的生物级联反应。总之，我们的研究探讨了NCAPG在HER2+ BC中曲妥珠单抗耐药中的关键作用及其潜在机制，并表明NCAPG既可以作为潜在的预后标志物，也可以作为有效克服曲妥珠单抗耐药的治疗靶点。
HER2+ breast cancer (BC) is characterized by rapid growth, early recurrence, early metastasis, and chemoresistance. Trastuzumab is the most effective treatment for HER2+ BC and effectively reduces the risk of recurrence and death of patients. Resistance to trastuzumab results in cancer recurrence and metastasis, leading to poor prognosis of HER2+ BC. In the present study, we found that non-structural maintenance of chromosome condensin 1 complex subunit G (NCAPG) expression was highly upregulated in trastuzumab-resistant HER2+ BC. Ectopic NCAPG was positively correlated with tumor relapse and shorter survival in HER2+ BC patients. Moreover, overexpression of NCAPG promoted, while silencing of NCAPG reduced, the proliferative and anti-apoptotic capacity of HER2+ BC cells both in vitro and in vivo, indicating NCAPG reduces the sensitivity of HER2+ BC cells to trastuzumab and may confer trastuzumab resistance. Furthermore, our results suggest that NCAPG triggers a series of biological cascades by phosphorylating SRC and enhancing nuclear localization and activation of STAT3. To summarize, our study explores a crucial role for NCAPG in trastuzumab resistance and its underlying mechanisms in HER2+ BC, and suggests that NCAPG could be both a potential prognostic marker as well as a therapeutic target to effectively overcome trastuzumab resistance.